The present invention is directed to ophthalmic compositions, particularly those provided as buffered, aqueous solutions. The subject compositions are useful as moisturizing and lubricating eye drops and as delivery vehicles for ophthalmic drugs.
Ophthalmic compositions used for the treatment of xe2x80x9cdry eyexe2x80x9d symptoms include demulcents (or humectants) for lubricating mucous membrane surfaces and for relieving dryness and irritation. The term xe2x80x9cdemulcentxe2x80x9d, as used herein is intended to mean an agent, usually a water-soluble polymer, which is applied topically to the eye to protect and lubricate mucous membrane surfaces and relieve dryness and irritation. Within this meaning, the terms xe2x80x9chumectantxe2x80x9d and xe2x80x9cwetting agentxe2x80x9d are also commonly used. Furthermore, it will be understood that some constituents possess several functional attributes. For example, cellulose derivatives are common demulcents, but are also used as xe2x80x9cviscosity increasing agentsxe2x80x9d. Similarly, glycerin is a known demulcent but is also used as a xe2x80x9ctonicity adjusting agentxe2x80x9d. Examples of the most widely used demulcents include: polyvinyl alcohol, polyvinyl pyrrolidone, cellulose derivatives and polyethylene glycol.
Specific examples of known ophthalmic compositions including various demulcents are provided below.
U.S. Pat. No. 5,591,426 to Dabrowski et al. discloses an ophthalmic solution useful as an artificial tear. The reference includes a specific example of a borate buffered, preserved (e.g. benzalkonium chloride), aqueous solution including the following three demulcents: 1) glycerin, 2) polyvinyl pyrrolidone, and 3) a cellulose derivative, e.g. hydroxypropyl methyl cellulose.
U.S. Pat. No. 5,106,615 to Dikstein discloses isotonic humectant eyedrops including glycerin, polyethylene glycol, or propylene glycol with an anionic polymer such as Carbomer 941.
U.S. Pat. No. 2,703,777 to Feinstein et al. generally describes a preserved, buffered, isotonic ophthalmic gel including: 1) a humectant, preferably glycerin (sorbitol and propylene glycol are also listed); 2) methyl cellulose, and 3) polyethylene glycol.
U.S. Pat. No. 4,029,817 to Blanco et al. discloses a contact lens preserving solution including propylene glycol in combination with polysorbate 80 and/or polyvinyl pyrrolidone. Similarly, U.S. Pat. No. 5,141,665 to Sherman discloses a contact lens cleaning, wetting and storing solution which includes propylene glycol as a wetting agent. Also, U.S. Pat. No. 4,525,346 to Stark discloses a borate buffered, preserved contact lens solution including propylene glycol.
U.S. Pat. Nos. 3,767,788; 3,767,789; 3,856,919; 3,907,985; 3,920,810; 3,947,573; 3,987,163 all to Rankin disclose ophthalmic solutions for the treatment of xe2x80x9cdye eyexe2x80x9d. These references generally teach the use of polyethylene oxide, polystyrene sulfonate, and polyacrylamide, with polyalkylene glycols, e.g. polyethylene glycol or propylene glycol. These references include specific example solutions including several demulcents combined with one another; namely, 1) polyethylene glycol, 2) polyvinyl pyrrolidone and a 3) cellulose derivative, e.g. hydroxy ethyl cellulose.
U.S. Pat. No. 3,549,747 to Krezanoski et al. discloses a preserved contact lens wetting solution including polyvinyl alcohol with a cellulose derivative, e.g. hydroxy ethyl cellulose. Similarly, U.S. Pat. No. 4,131,651 to Shah et al. discloses an ophthalmic solution for the treatment of dry eye which includes polyvinyl alcohol with a cellulose derivative. U.S. Pat. No. 4,120,949 to Bapatla et al. discloses a preserved ophthalmic solution including 1) polyvinyl alcohol, 2) polyvinylpyrrolidone, and 3) one or more cellulose derivatives. Also similarly, U.S. Pat. No. 4,409,205 to Shively discloses a specific example of a preserved ophthalmic solution including: polyvinyl alcohol, polyethylene glycol 6000, and dextrose. This reference also generally discloses the use of tonicity adjusting agents selected from the group of: mannitol, sorbitol, dextrose, sucrose, urea, and glycerin.
Techniques for formulating gels for delivering ophthalmically active drugs topically are known in the art, see for example GB-A-No. 2013084 disclosing aqueous pre-formed pharmaceutical gels for application to the conjunctival sac of the eye, and GB-A-No. 1571832 and EP-A-No. 0126684 disclosing drug delivery systems in the form of liquids which gel in situ when warmed by the body of the patient and useful in the treatment of a variety of ocular conditions. Similarly, U.S. Pat. No. 4,888,168 to Potts et al. and U.S. Pat. No. 5,800,807 to Hu et al. disclose a gel systems for delivering ophthalmic drugs.
The goal of designing an ophthalmic gel is to make the gel sufficiently flowable that the gel can be conveniently applied to the eye, while at the same time providing a gel that is viscous enough to prolong residence time (contact time) in the eye. But the viscosity at body temperature of known in situ gelling systems can be difficult to predict with certainty. Gels having viscosities above about 55 centipoise (cps) can be uncomfortable and aesthetically unattractive in the eye. For this reason, it is critical to provide an ophthalmic gel that provides the desired residence time while avoiding the discomfort and unattractive cosmetic appearance of a substantially solidified gel.
Thus it would be desirable to provide an ophthalmic gel that improves the contact time between the target ocular tissue and an active pharmaceutical agent, while also overcoming the problems associated with high viscosity gels. It would also be desirable to improve the durability and the useful life of the gel composition once formed to further prolong contact time with the target ocular tissue.
The present invention provides an ophthalmic gel composition that effectively prolongs residence time in the eye while at the same time being more comfortable and easier to apply. This invention relates to the treatment of eye conditions using pharmaceutical preparations that gel in situ when applied to the patient. Suitable active pharmaceutical agents include beta blockers, carbonic anhydrase inhibitors, ophthalmic decongestants, antihistamines, antibiotics and antiinflamatories, merely to name a few.
In one embodiment, the subject composition is provided as a buffered, aqueous solution which includes a demulcent, preferably a cellulose derivative. The subject composition may be unpreserved (provided in a single dose format), or may be preserved, e.g. with benzylalkonium chloride, PHMB, sorbic acid, etc.
The invention provides, in one embodiment, an ophthalmic aqueous composition for topical administration, comprising:
(a) a block copolymer of propylene oxide and ethylene oxide in concentration sufficient to provide viscosity of less than about 25 centipoise at ambient temperature and viscosity of from about 25 to about 55 centipoise when applied topically to a patient; and
(b) hydroxypropyl methylcellulose in concentration sufficient to improve the durability of a gel formed by the block copolymer.
The block copolymer of propylene oxide and ethylene oxide preferably comprises at least one propylene oxide block sandwiched between two ethylene oxide blocks. This is commonly referred to as an ABA block copolymer. In a particularly preferred embodiment, the composition of the block has the chemical formula:
HOxe2x80x94(R1)kxe2x80x94(R2)mxe2x80x94(R3)nxe2x80x94]pxe2x80x94H 
where
R1 is xe2x80x94CH2CH2Oxe2x80x94;
R2 is xe2x80x94CH3CH CH2Oxe2x80x94;
R3 is xe2x80x94CH2CH2Oxe2x80x94;
k is from 2 to 128;
m is from 16 to 67; and
p is from 2 to 128.
The most preferred block copolymeric surfactants include:
HOxe2x80x94(R1)kxe2x80x94(R2)mxe2x80x94(R3)nxe2x80x94]pxe2x80x94H 
where
R1 is xe2x80x94CH2CH2Oxe2x80x94;
R2 is xe2x80x94CH3CH CH2Oxe2x80x94;
R3 is xe2x80x94CH2CH2Oxe2x80x94;
k is about 98 (average);
m is about 67 (average); and
p is about 98 (average).
The methylcellulose useful in the present invention is preferably hydroxpropyl methylcellulose. The preferred hydroxypropyl methylcellulose composition preferred for use in the present invention has the chemical formula shown below. One particularly preferred group of methylcellulose compositions is sold under the tradename xe2x80x9cMethocelxe2x80x9d by the Dow Chemical Company of Midland, Mich. Examples of useful methylcellulose compositions include Methocel A, E, F, J and K, as well as the Methocel 310 series of compositions. For the composition of the present invention, Methocel E is the most preferred Methocel brand composition. 
The most preferred METHOCEL is METHOCEL E.
The invention provides, in another embodiment, a method for administering an ophthalmic drug comprising topically applying a sterile ophthalmic solution to a patient""s eye, said solution comprising (a) a block copolymer of propylene oxide and ethylene oxide in concentration sufficient to provide viscosity of less than about 25 centipoise at ambient temperature and viscosity of from about 25 to about 55 centipoise when applied topically to a patient; and (b) hydroxypropyl methylcellulose in concentration sufficient to improve the durability of the gel formed by the block copolymer.